Importance of a Synperiplanar Stepwise Mechanism through Neutral Intermediates in the Aminolysis of Monocyclic β-Lactams:  A Theoretical Analysis

The ring opening of 2-azetidinone via a neutral CH₃NH₂-assisted aminolysis process is studied using different quantum chemical methods (MP2/6-31G**, B3LYP/6-31G**, and G2(MP2,SVP) levels of theory) as a further step to the theoretical investigation of the aminolysis reaction of β-lactam antibiotics. The exploration of the corresponding potential energy surface (PES) renders a concerted pathway and two different stepwise routes through several neutral tetrahedral intermediates. A nonconcerted route involving an N inversion of a tetrahedral intermediate is the most favored mechanism, the formation of a first antiperiplanar intermediate constituting the rate-determining step with an activation energy in solution of 42.2 kcal/mol. The N-inversion process leads to a synperiplanar intermediate whose ring opening requires 40.9 kcal/mol as Gibbs energy barrier. This stepwise mechanism is favored by 5.2 and 6.0 kcal/mol with respect to the concerted mechanism and the alternative antiperiplanar stepwise process, respectively. Reaction coordinate calculations indicate that zwitterionic structures in solution would be extremely unstable intermediates to play a significant kinetic role in the process. The experimental linear Brønsted plots on the pK_a of monoamines for the aminolysis of both monocyclic and bicyclic β-lactams are well rationalized in terms of an ionic formal partitioning that describes the main transition structures as composed of a methylammonium cation and a 1,1-amino alcoholate anion. According to our analyses, the methyl-induced stabilization of the TSs stems mainly from the intrinsic stabilization achieved by the corresponding ionic moieties, especially the catalytic one. From the above results, it is inferred that monocyclic β-lactams would react preferentially along a stepwise mechanism. For bicyclic β-lactams in which the N-inversion is impeded, the concerted route could be slightly favored although other factors not considered in this work could have an important kinetic role.